title: Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses.
abstract: It currently is believed that vitamin A, retinol, functions through active metabolites: the visual chromophore 11-cis-retinal, and retinoic acids, which regulate gene transcription. Retinol circulates in blood bound to retinol-binding protein (RBP) and is transported into cells by a membrane protein termed "stimulated by retinoic acid 6" (STRA6). We show here that STRA6 not only is a vitamin A transporter but also is a cell-surface signaling receptor activated by the RBP-retinol complex. Association of RBP-retinol with STRA6 triggers tyrosine phosphorylation, resulting in recruitment and activation of JAK2 and the transcription factor STAT5. The RBP-retinol/STRA6/JAK2/STAT5 signaling cascade induces the expression of STAT target genes, including suppressor of cytokine signaling 3 (SOCS3), which inhibits insulin signaling, and peroxisome proliferator-activated receptor gamma (PPARγ), which enhances lipid accumulation. These observations establish that the parental vitamin A molecule is a transcriptional regulator in its own right, reveal that the scope of biological functions of the vitamin is broader than previously suspected, and provide a rationale for understanding how RBP and retinol regulate energy homeostasis and insulin responses.
authors.affiliation: Department of Pharmacology and Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Berry
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.forename: Avijit
authors.initials: A
authors.lastname: Majumdar
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012177:Retinol-Binding Proteins / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D007328:Insulin; D008565:Membrane Proteins; D012177:Retinol-Binding Proteins; D050799:STAT5 Transcription Factor; C519685:STRA6 protein, human; C108001:Stra6 protein, mouse; D014280:Triglycerides; D014801:Vitamin A; C507924:JAK2 protein, human; D053614:Janus Kinase 2